Mesothelial Origin of Creeping Fat Progenitors in Crohn's Disease

Abstract

Background: Our understanding of the origin of human adipose tissue is limited. In this regard, the development of in Crohn's disease is particularly puzzling. The mesothelium has recently emerged as a source of visceral adipose tissue in rodents. We therefore sought to investigate the mesothelial properties of human visceral and subcutaneous adipose tissue and progenitor cells. Additionally, we explored whether the dysfunctional environment of obesity and Crohn's disease influences adipose tissue and the mesothelial/mesenchymal properties of its precursors. Methods: We used a tandem transcriptomic/proteomic approach to evaluate mesothelial and mesenchymal markers in adipose tissue, both in subjects covering a wide range of body-mass index and in patients with Crohn's disease. We also isolated adipose tissue precursors (adipose-derived stem cells) from lean, obese and Crohn's disease fat depots and assessed their mesothelial/mesenchymal properties. Findings: Several mesothelial signature genes (LRRN4, MSLN, KRT8, CDH1, and WT1) were significantly upregulated in human visceral fat when compared to equivalent subcutaneous tissue. These data were corroborated at the protein level by proteomic analysis. No significant differences in mesothelial gene expression were found in visceral fat tissue between lean, obese and morbid-obese subjects and patients with Crohn's disease. However adipose-derived stem cells from mesenteric creeping fat had a markedly distinct mesothelial gene profile as compared with equivalent lean-derived cells, with significantly higher expression of the hallmark mesothelial genes MSLN and WT1, supporting a mesothelial nature of these cells. Interpretation: We present the first direct evidence for a mesothelial signature for human visceral adipose tissue and its progenitor cells, specifically for creeping fat in Crohn's disease. Funding Statement: This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities (PI14/00228 and PI17/01503 to JV, SAF2015-65019-R to SF-V, BFU2015-70454-REDT and BFU2017- 90578-REDT to SF-V and MMM, BFU2016-76711-R to MMM and PI15/00143 and PI18/00037 to CS) co-financed by the European Regional Development Fund (ERDF). The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. AM is a recipient of a postdoctoral fellowship from FJCI-2014-23060 and IJCI-2016-30572. SF-V acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) of the Fondo de Investigacion Sanitaria, co-financed by the ERDF. C.S. acknowledges support from the ‘‘Ramon y Cajal’ program from MINECO (RYC2013-13186), cofinanced by the ERDF. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants gave their informed consent, and the study was reviewed and approved by the ethics and research committee of University Hospital Joan XXIII in accordance with the tenets of the Helsinki Declaration. Participants of the fat sampling gave their informed written consent. The ethics and research committee of the Hospital Clinico Virgen de la Victoria approved the protocol.